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PGE 2 induces endothelial cells migration through FGFR-1 activation. A, sparse, synchronized endothelial cells were exposed to PGE 2 or Misoprostol (1-1000 nM). Data are reported as cell number counted/well. (n 4). p 0.01 (*) and p 0.001 (**) versus 0.1% serum. B, CVEC were treated with SU5614 (10 M) or SU5402 (10 M), then stimulated with PGE 2 (100 nM) for 4 h. Cell migration was measured as cell number counted/well. **, p 0.001 versus PGE 2 alone (n 3).
Source publication
Prostaglandin E(2) (PGE(2)) behaves as a mitogen in epithelial tumor cells as well as in many other cell types. We investigated the actions of PGE(2) on microvascular endothelial cells (capillary venular endothelial cells) with the purpose of delineating the signaling pathway leading to the acquisition of the angiogenic phenotype and to new vessel...
Contexts in source publication
Context 1
... to PGE 2 was concentration-related, maximal effect being reached at 100 nM (a concentration used throughout this work). Misoprostol, a metabolically stable PGE 2 analogue, reproduced the effect of the natural ligand, suggesting that PGE 2 is stable under the conditions used, and its effects may not be attributed to its derivative products (Fig. 1A). In light of these results we won- dered whether PGE 2 activity might involve canonical pathways of angiogenesis such as those elicited by the FGF-2 or the VEGF. We, therefore, measured PGE 2 -induced cell migration in the presence of antagonists of their respective receptors (FGFR-1 and VEGFR-2). Indeed, FGFR-1 blockade by SU5402 (10 ...
Context 2
... such as those elicited by the FGF-2 or the VEGF. We, therefore, measured PGE 2 -induced cell migration in the presence of antagonists of their respective receptors (FGFR-1 and VEGFR-2). Indeed, FGFR-1 blockade by SU5402 (10 M) abolished cell migration, whereas application of SU5614 (10 M), a blocker of VEGFR-2, did not modify PGE 2 action (Fig. ...
Context 3
... indicating that EP3 receptor is the predominant subtype involved in PGE 2 -induced phosphorylation of FGFR-1. Transfection of all EP receptor subtypes in CHO-FGFR-1 resulted in EPs overexpression but did not allow monitoring of FGFR-1 transactivation in response to PGE 2 for the absence of FGF-2 expression in this cell model (see supplemental Figs. S1 and S2). Thus, to address more spe- cifically the role of EP3 in FGFR-1 activation in response to PGE 2 , human umbilical venular endothelial cells were selected, since this cell model has the capability of expressing c-Src and FGF-2 but does not express the EP3 receptor (32). Stimulation of human umbilical venular endothelial cells with 100 ...
Citations
... On the other hand, there are more and more studies showing that EP3 can promote the development of tumors. Finetti et al. found that EP3 is involved in regulating the formation of tumor blood vessels [26]. Amano et al. found that in an EP3deficient mouse tumor model, tumor angiogenesis and tumor cell growth were effectively inhibited [13]. ...
Simple Summary
Due to the lack of effective early diagnostic markers for lung cancer and the rich blood circulation in the lungs, it is very easy to cause lymph node metastasis and distant metastasis of lung cancer, making lung cancer as one of the top ten cancer types with the highest mortality rate in the world. This study found that MAPK15 is highly expressed in the tissues of patients with lung adenocarcinoma lymph node metastasis, and MAPK15 interacts with p50 to regulate the expression of EP3 at the transcriptional level, thereby promoting cancer cell migration. This suggests that MAPK15 plays a key role in the metastasis of lung cancer cells, and MAPK15 can be used as a molecular marker for the early diagnosis or prognosis assessment of lung cancer. Its molecular mechanism for regulating lung cancer metastasis can provide valuable information and insights on novel therapeutic options at molecular levels.
Abstract
Studying the relatively underexplored atypical MAP Kinase MAPK15 on cancer progression/patient outcomes and its potential transcriptional regulation of downstream genes would be highly valuable for the diagnosis, prognosis, and potential oncotherapy of malignant tumors such as lung adenocarcinoma (LUAD). Here, the expression of MAPK15 in LUAD was detected by immunohistochemistry and its correlation with clinical parameters such as lymph node metastasis and clinical stage was analyzed. The correlation between the prostaglandin E2 receptor EP3 subtype (EP3) and MAPK15 expression in LUAD tissues was examined, and the transcriptional regulation of EP3 and cell migration by MAPK15 in LUAD cell lines were studied using the luciferase reporter assay, immunoblot analysis, qRT-PCR, and transwell assay. We found that MAPK15 is highly expressed in LUAD with lymph node metastasis. In addition, EP3 is positively correlated with the expression of MAPK15 in LUAD tissues, and we confirmed that MAPK15 transcriptionally regulates the expression of EP3. Upon the knockdown of MAPK15, the expression of EP3 was down-regulated and the cell migration ability was decreased in vitro; similarly, the mesenteric metastasis ability of the MAPK15 knockdown cells was inhibited in in vivo animal experiments. Mechanistically, we demonstrate for the first time that MAPK15 interacts with NF-κB p50 and enters the nucleus, and NF-κB p50 binds to the EP3 promoter and transcriptionally regulates the expression of EP3. Taken together, we show that a novel atypical MAPK and NF-κB subunit interaction promotes LUAD cell migration through transcriptional regulation of EP3, and higher MAPK15 level is associated with lymph node metastasis in patients with LUAD.
... PGE 2 can induce microvascular endothelial cells to express angiogenic factors, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), to support neovascular growth [21]. We found that the expression of EP2 in NB is strongly associated with VEGF, endoglin (ENG) and platelet endothelial cell adhesion molecule 1 (PECAM-1), which are the three markers of microvascular proliferation [20]. ...
... In fact, EP3 is considerably downregulated in nonsurvival NB patients when compared to survival cohorts, suggesting that EP3 negatively correlates with the aggressiveness of NB [20]. These findings together raise the possibility that PGE 2 may engage different receptor subtypes in different tumor cells, stroma cells, and vascular endothelial cells and function synergistically with other factors such as hypoxiainducible factor and fibroblast growth factor receptor in orchestrating the angiogenesis under physiological and pathological conditions [21,23]. However, EP2 likely is the leading receptor subtype that mediates the PGE 2 -promoted angiogenesis during NB progression. ...
Neuroblastoma (NB) is the most common pediatric extracranial solid tumor arising from neural crest cells of the developing sympathetic nervous system. Despite marked advances in cancer treatment, the survival rate of high-risk NB remains unsatisfactory. As a key pro-inflammatory mediator regulating tumor microenvironment, prostaglandin E2 (PGE2) promotes NB proliferation, angiogenesis, and immune evasion via acting on four G protein-coupled receptors, particularly the EP2 subtype. Recent studies have been vigorously focused on developing and evaluating compounds targeting PGE2-regulated tumor inflammation in animal models of NB. In this review, we revisit these translational efforts and examine the feasibility of pharmacological inhibition of enzymes responsible for PGE2 biosynthesis or its signaling receptors as emerging therapeutic strategies for NB. We also explore the potential downstream oncogenic pathways upon the activation of PGE2 receptors, aiming to bridge the knowledge gap between tumorigenesis and the role of elevated PGE2/EP2 signaling, which is widely observed in high-risk NBs.
... Nonetheless, whether the EP4 receptor signaling down-or upregulates the growth of NB remains to be determined. PGE 2 signaling via EP2 receptor has emerged as an essential contributor to tumor growth engaging mechanisms including, but not limited to, (1) inducing reactive mediators for tumor cell growth, including pro-inflammatory cytokines and growth factors (Donnini et al., 2007;Jiang and Dingledine, 2013b;Ma et al., 2015;Merz et al., 2016); (2) promoting angiogenesis via activating VEGF and fibroblast growth factor (Finetti et al., 2008;Kamiyama et al., 2006;Trau et al., 2016); and (3) creating immunosuppressive microenvironments that allow tumor cells to escape immunosurveillance (Aoki and Narumiya, 2017;Khan et al., 2022;O'Brien et al., 2014). The molecular mechanisms by which PGE 2 /EP2 signaling promotes NB progression are not fully understood. ...
Prostaglandin E2 (PGE2) promotes tumor cell proliferation, migration, and invasion, fostering an inflammation-enriched microenvironment that facilitates angiogenesis and immune evasion. However, the PGE2 receptor subtype (EP1–EP4) involved in neuroblastoma (NB) growth remains elusive. Herein, we show that the EP2 receptor highly correlates with NB aggressiveness and acts as a predominant Gαs-coupled receptor mediating PGE2-initiated cyclic AMP (cAMP) signaling in NB cells with high-risk factors, including 11q deletion and MYCN amplification. Knockout of EP2 in NB cells blocks the development of xenografts, and its conditional knockdown prevents established tumors from progressing. Pharmacological inhibition of EP2 by our recently developed antagonist TG6-129 suppresses the growth of NB xenografts in nude mice and syngeneic allografts in immunocompetent hosts, accompanied by anti-inflammatory, antiangiogenic, and apoptotic effects. This proof-of-concept study suggests that the PGE2/EP2 signaling pathway contributes to NB malignancy and that EP2 inhibition by our drug-like compounds provides a promising strategy to treat this deadly pediatric cancer.
... Previously, NGF treatment stimulated PGE release for up to 8 h in theca cells extracted from bovine preovulatory follicles (3). Prostaglandin E 2 is synthesized by PGES and acts as a pro-angiogenic molecule in vascular endothelium by recruiting the paracrine-autocrine mechanism characteristic of endothelium cells, resulting in vascular remodeling (27). Prostaglandin E 2 also supports luteal progesterone production in cattle (28), potentially through increased CL vascularity (29). ...
Nerve growth factor-β (NGF) is critical for ovulation in the mammalian ovary and is luteotrophic when administered systemically to camelids and cattle. This study aimed to assess the direct effects of purified bovine NGF on steroidogenesis and angiogenic markers in the bovine pre-ovulatory follicle. Holstein heifers (n = 2) were synchronized with a standard protocol, and heifers with a preovulatory follicle (≥ 12 mm) had the ovary containing the dominant follicle removed via colpotomy. Pre-ovulatory follicles were dissected into 24 pieces containing theca and granulosa cells that were randomly allocated into culture media supplemented with either purified bovine NGF (100 ng/mL) or untreated (control) for 72 h. The supernatant media was harvested for quantification of progesterone, testosterone, and estradiol concentrations, whereas explants were subjected to mRNA analyses to assess expression of steroidogenic and angiogenic markers. Treatment of follicle wall pieces with NGF upregulated gene expression of steroidogenic enzyme HDS17B (P = 0.04) and increased testosterone production (P < 0.01). However, NGF treatment did not alter production of progesterone (P = 0.81) or estradiol (P = 0.14). Consistently, gene expression of steroidogenic enzymes responsible for producing these hormones (STAR, CYP11A1, HSD3B, CYP17A1, CYP19A1) were unaffected by NGF treatment (P ≥ 0.31). Treatment with NGF downregulated gene expression of the angiogenic enzyme FGF2 (P = 0.02) but did not alter PGES (P = 0.63), VEGFA (P = 0.44), and ESR1 (P = 0.77). Collectively, these results demonstrate that NGF from seminal plasma may interact directly on the theca and granulosa cells of the bovine pre-ovulatory follicle to stimulate testosterone production, which may be secondary to theca cell proliferation. Additionally, decreased FGF2 expression in NGF-treated follicle wall cells suggests hastened onset of follicle wall cellular remodeling that occurs during early luteal development.
... The PTGS-2 gene and its product encode Cyclooxygenase-2 (COX-2) enzyme, as a vasoactive factor, having an important role in angiogenesis and implantation through VEGF regulation. Therefore it has a key role in successful implantation and early pregnancy (Finetti et al., 2008). It has been shown that mutations in PTGS-2 can lead to several defects in the reproductive system, such as implantation failure (Matsumoto et al., 2002). ...
Recurrent Miscarriage (RM), the most typical pregnancy complication, is diagnosed as the three consecutive losses of pregnancy during the first trimester. According to the epidemiologic studies about1% to 2% of women experience recurrent pregnancy loss. Defects in vascular formation and angiogenesis are among the causes leading to an increased risk of pregnancy loss. Angiogenesis process is one of the most important steps of embryogenesis, characterized by the formation of new blood vessels from previous blood vessels. Failure at any stage of the angiogenesis process from starting and sprouting vessels to maturation, can reduce the chances of the fetus surviving due to a lack of exchange of nutrients, oxygen, and waste products. Some pathways associated with angiogenesis such as HIF-1α/VEGF signaling pathway are very important in fetal and placental development. RM has multiple etiology among which we will discuss how genetic variations of angiogenic factors in association with HIF-1α/VEGF signaling pathway are connected with RM. We will also review some therapeutic targets associated with this pathway.
... Tumor growth and migration are also depending on angiogenesis for transporting nutrients and chemical signals. The activation of PGE 2 -EP2/4 could promote angiogenesis through CXCR4 and upregulation of Src [56,57]. Additionally, Orai1 has recently been identified as one of the downstream molecules of the EP4/PI3K pathway, which is responding to PGE 2 -induced cancer cell migration [58]. ...
Delta-5 desaturase (D5D) is a rate-limiting enzyme that introduces double-bonds to the delta-5 position of the n-3 and n-6 polyunsaturated fatty acid chain. Since fatty acid metabolism is a vital factor in cancer development, several recent studies have revealed that D5D activity and expression could be an independent prognostic factor in cancers. However, the mechanistic basis of D5D in cancer progression is still controversial. The classical concept believes that D5D could aggravate cancer progression via mediating arachidonic acid (AA)/prostaglandin E2 production from dihomo-γ-linolenic acid (DGLA), resulting in activation of EP receptors, inflammatory pathways, and immunosuppression. On the contrary, D5D may prevent cancer progression through activating ferroptosis, which is iron-dependent cell death. Suppression of D5D by RNA interference and small-molecule inhibitor has been identified as a promising anti-cancer strategy. Inhibition of D5D could shift DGLA peroxidation pattern from generating AA to a distinct anti-cancer free radical byproduct, 8-hydroxyoctanoic acid, resulting in activation of apoptosis pathway and simultaneously suppression of cancer cell survival, proliferation, migration, and invasion. Hence, understanding the molecular mechanisms of D5D on cancer may therefore facilitate the development of novel therapeutical applications. Given that D5D may serve as a promising target in cancer, in this review, we provide an updated summary of current knowledge on the role of D5D in cancer development and potentially useful therapeutic strategies.
... Increased PGE 2 /COX-2 levels raise the VEGF production and angiogenesis of the cancer cells. PGE 2 regulates angiogenesis via activation of fibroblast growth factor receptor-1 [290]. PGE 2 produced by the host drives the growth, angiogenesis, and metastasis of the cancer cells' bone and soft tissue in vivo. ...
The dysregulation of fat metabolism is involved in various disorders, including neurodegenerative, cardiovascular, and cancers. The uptake of long-chain fatty acids (LCFAs) with 14 or more carbons plays a pivotal role in cellular metabolic homeostasis. Therefore, the uptake and metabolism of LCFAs must constantly be in tune with the cellular, metabolic, and structural requirements of cells. Many metabolic diseases are thought to be driven by the abnormal flow of fatty acids either from the dietary origin and/or released from adipose stores. Cellular uptake and intracellular trafficking of fatty acids are facilitated ubiquitously with unique combinations of fatty acid transport proteins and cytoplasmic fatty acid-binding proteins in every tissue. Extensive data are emerging on the defective transporters and metabolism of LCFAs and their clinical implications. Uptake and metabolism of LCFAs are crucial for the brain's functional development and cardiovascular health and maintenance. In addition, data suggest fatty acid metabolic transporter can normalize activated inflammatory response by reprogramming lipid metabolism in cancers.
Here we review the current understanding of how LCFAs and their proteins contribute to the pathophysiology of three crucial diseases and the mechanisms involved in the processes.
... Other reviews describe separate pathways where cytokines, for example, directly mediate leakage independent of VEGF ( Figure 1) [22][23][24][25]. There is literature supporting both views-for example, the cytokine prostaglandin E2 can directly cause vascular leakage and proliferation but can also upregulate VEGF [26][27][28][29]. Both pathways likely play some role in the development of leakage. ...
Anti-vascular endothelial growth factor (anti-VEGF) therapy currently plays a central role in the treatment of numerous retinal diseases, most notably exudative age-related macular degeneration (eAMD), diabetic retinopathy and retinal vein occlusions. While offering significant functional and anatomic benefits in most patients, there exists a subset of 15–40% of eyes that fail to respond or only partially respond. For these cases, various treatment options have been explored with a range of outcomes. These options include steroid injections, laser treatment (both thermal therapy for retinal vascular diseases and photodynamic therapy for eAMD), abbreviated anti-VEGF treatment intervals, switching anti-VEGF agents and topical medications. In this article, we review the effectiveness of these treatment options along with a discussion of the current research into future directions for anti-VEGF-resistant eyes.
... Endothelial trophism is guaranteed by the response to vasoactive and growth factors produced by surrounding tissues or autocrinally by the same ECs. Among the various examples, we and others have contributed to characterizing the beneficial effects on vascular endothelium by NO derived from eNOS, bradykinin, substance P, vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), prostaglandin E2, H2S [11][12][13][14][15]. The molecular mechanisms responsible for cell survival, proliferation, migration and functioning include eNOS/NO/cGMP/protein kinase G (PKG), PI-3K/Akt, MAPK/ERK1/2 and gene transcription of autocrine factors as FGF-2 [7]. ...
The vascular endothelium consists of a single layer of squamous endothelial cells (ECs) lining the inner surface of blood vessels. Nowadays, it is no longer considered as a simple barrier between the blood and vessel wall, but a central hub to control blood flow homeostasis and fulfill tissue metabolic demands by furnishing oxygen and nutrients. The endothelium regulates the proper functioning of vessels and microcirculation, in terms of tone control, blood fluidity, and fine tuning of inflammatory and redox reactions within the vessel wall and in surrounding tissues. This multiplicity of effects is due to the ability of ECs to produce, process, and release key modulators. Among these, gasotransmitters such as nitric oxide (NO) and hydrogen sulfide (H2S) are very active molecules constitutively produced by endotheliocytes for the maintenance and control of vascular physiological functions, while their impairment is responsible for endothelial dysfunction and cardiovascular disorders such as hypertension, atherosclerosis, and impaired wound healing and vascularization due to diabetes, infections, and ischemia. Upregulation of H2S producing enzymes and administration of H2S donors can be considered as innovative therapeutic approaches to improve EC biology and function, to revert endothelial dysfunction or to prevent cardiovascular disease progression. This review will focus on the beneficial autocrine/paracrine properties of H2S on ECs and the state of the art on H2S potentiating drugs and tools.
... In addition, based on the observation that brain COX-2 expression is induced under prolonged moderate hypoxia (Benderro & LaManna, 2014;LaManna et al., 2006), the role for COX in brain hypoxia-induced angiogenesis has been proposed. This hypothesis is further supported by the direct effect of COX products on a number of angiogenic factors (Fukuda et al., 2003;Jurek et al., 2004;Tsujii et al., 1998;Tuncer & Banerjee, 2015;Zhao et al., 2012) (Finetti et al., 2008;Kang et al., 2007;Katori et al., 1998;Leahy et al., 2000;Salcedo et al., 2003), as well as indirect COX effect on angiogenesis through MAPK pathway (Cho & Choe, 2020;Riquelme et al., 2015). ...
... The 3D Z-stack images were analyzed using a TubeAnalyst macro (IRB Barcelona) available for Fiji (Image J) software. (Conconi et al., 2004;Katori et al., 1998;Leahy et al., 2000;Nakatsu et al., 2003;Presta et al., 1986;Thompson et al., 1988), and several studies indicated bFGF/FGFR1 regulation through COX activity (Finetti et al., 2008;Katori et al., 1998;Leahy et al., 2000). However, to the best of our knowledge, no previous studies addressed this signaling in brain tissue under hypoxia. ...
... attenuates VEGF levels, while exogenous PGE 2 reverses the inhibitory effects of NS-398 (Zhao et al., 2012). However, exogenous PGE 2 has no effect on VEGFR2 in microvascular endothelial cell cultures (Finetti et al., 2008), and COX-2 inhibition has no effect on VEGF levels in cortex or white matter in rabbit pups (Ballabh et al., 2007). Importantly, VEGF and bFGF signaling is additionally regulated through peroxisome proliferator-activated receptors (PPARs) (Bishop-Bailey, 2011;Piqueras et al., 2007;Wang et al., 2006) that is in turn up-regulated through another COX product PGD 2 and its non-enzymatic metabolite, Δ(12)-PGJ 2 (Fujimori, 2012), highlighting additional potential mechanism for angiogenesis regulation by COX activity. ...
Although cyclooxygenase (COX) role in cancer angiogenesis has been studied, little is known about its role in brain angioplasticity. In the present study, we chronically infused mice with ketorolac, a non‐specific COX inhibitor that does not cross the blood–brain barrier (BBB), under normoxia or 50% isobaric hypoxia (10% O2 by volume). Ketorolac increased mortality rate under hypoxia in a dose‐dependent manner. Using in vivo multiphoton microscopy, we demonstrated that chronic COX inhibition completely attenuated brain angiogenic response to hypoxia. Alterations in a number of angiogenic factors that were reported to be COX‐dependent in other models were assayed at 24‐hr and 10‐day hypoxia. Intriguingly, hypoxia‐inducible factor 1 was unaffected under COX inhibition, and vascular endothelial growth factor receptor type 2 (VEGFR2) and C‐X‐C chemokine receptor type 4 (CXCR4) were significantly but slightly decreased. However, a number of mitogen‐activated protein kinases (MAPKs) were significantly reduced upon COX inhibition. We conclude that additional, angiogenic factor‐independent mechanism might contribute to COX role in brain angioplasticity, probably including mitogenic COX effect on endothelium. Our data indicate that COX activity is critical for systemic adaptation to chronic hypoxia, and BBB COX is essential for hypoxia‐induced brain angioplasticity. These data also indicate a potential risk for using COX inhibitors under hypoxia conditions in clinics. Further studies are required to elucidate a complete mechanism for brain long‐term angiogenesis regulation through COX activity.
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